Process for preparing phenoxyphenylsulfonyl halides

ABSTRACT

A process for preparing phenoxyphenylsulfonyl halides, which are useful intermediates for the preparation of matrix metalloproteinase inhibitors.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to a process for preparingphenoxyphenylsulfonyl halides, which are useful intermediates for thepreparation of matrix metalloproteinase inhibitors and to intermediatesthereof.

[0002] Inhibitors of matrix metalloproteinase (MMP) are known to beuseful for the treatment of a condition selected from the groupconsisting of arthritis (including osteoarthritis and rheumatoidarthritis), inflamamtory bowel disease, Crohn's disease, emphysema,acute respiratory distress syndrome, asthma, chronic obstructivepulmonary disease, Alzheimers disease, organ transplant toxicity,cachexia, allergic reactions, allergic contact hypersensitivity cancer,tissue ulceration, restenosis, periodontal disease, epidermolysisbullosa, osteoporosis loosening of artificial joint implants,atherosclerosis (including atherosclerotic plaque rupture), aorticaneurysm (including abdominal aortic aneurysm and brain aorticaneurysm), congestive heart failure, myocardial infarction, stroke,cerebral ischemia, head trauma, spinal cord injury, neuro-degenerativedisorders (acute and chronic), autoimmune disorders, Huntington'sdisease, Parkinson's disease, migraine, depression, peripheralneuropathy, pain, cerebral amyloid angiopathy, nootropic or cognitionenhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocularangiogenesis, corneal injury, macular degeneration, abnormal woundhealing, burns, diabetes, tumor invasion, tumor growth, tumormetastasis, corneal scarring, scleritis, AIDS, sepsis, septic shock andother diseases characterized by inhibition of metalloproteinase or ADAM(including TNF-α) expression. In addition, the products which can beprepared from the compounds and processes of the present invention maybe used in combination therapy with standard non-steroidalanti-inflammatory drugs (hereinafter NSAID'S), COX-2 inhibitors andanalgesics for the treatment of arthritis, and in combination withcytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide,taxol, taxotere and alkaloids, such as vincristine, in the treatment ofcancer.

[0003] Matrix metalloproteinase inhibitors are well known in theliterature. Specifically, PCT publication WO 96/33172 published Oct. 24,1996, refers to cyclic arylsulfonylamino hydroxamic acids that areuseful as MMP inhibitors. U.S. Pat. No. 5,672,615, PCT Publication WO97/20824, PCT Publication WO 98/08825, PCT Publication WO 98/27069 andPCT Publication WO 98/34918, published Aug. 13, 1998, entitled“Arylsulfonyl Hydroxamic Acid Derivatives” all refer to cyclichydroxamic acids that are useful as MMP inhibitors. PCT Publications WO96/27583 and WO 98/07697, published Mar. 7, 1996 and Feb. 26, 1998,respectively, refer to arylsulfonyl hydroxamic acids. PCT Publication WO98/03516, published Jan. 29. 1998 refers to phosphinates with MMPactivity. PCT Publication WO 98/34915, published Aug. 13, 1998, entitled“N-Hydroxy-b-Sulfonyl Propionamide Derivatives,” refers topropionylhydroxamides as useful MMP inhibitors PCT Publication WO98/33768, published Aug. 6, 1998, entitled “Arylsulfonylamino HydroxamicAcid Derivatives,” refers to N-unsubstituted arylsulfonylaminohydroxamic acids. PCT Publication WO 98/30566, published Jul. 16, 1998,entitled “Cyclic Sulfone Derivatives,” refers to cyclic sulfonehydroxamic acids as MMP inhibitors. U.S. Provisional Patent Application60/55208, filed Aug. 8, 1997, refers to biaryl hydroxamic acids as MMPinhibitors. U.S. Provisional Patent Application Serial No. 60/55207,filed Aug. 8, 1997, entitled “Aryloxyarylsulfonylamino Hydroxamic AcidDerivatives,” refers to aryloxyarylsulfonyl hydroxamic acids as MMPinhibitors. U.S. Provisional Patent Application 60/62766, filed Oct. 24,1997, entitled “The Use of MMP-13 Selective Inhibitors For The Treatmentof Osteoarthritis and Other MMP Mediated Disorders,” refers to the useof MMP-13 selective inhibitors to treat inflammation and otherdisorders. U.S. Provisional Patent Application Serial No. 60/68261,filed Dec. 19, 1997, refers to the use of MMP inhibitors to treatangiogenesis and other disorders. Each of the above referencedpublications and applications is hereby incorporated by reference in itsentirety.

[0004] The present inventors have now discovered a convenient processfor preparing (4-fluorophenoxy-phenyl)-sulfonyl chloride in three stepsfrom 4chloro-sulfonyl chloride.

SUMMARY OF THE INVENTION

[0005] The present invention relates to a compound of the formula

[0006] wherein R is H, Li, Na, K, Mg, or NH₄, preferably Na, K, or Mg,most preferably Na.

[0007] Other preferred compounds of the invention include compounds ofthe formula

[0008] wherein m is an interger from 1-3;

[0009] wherein R² is fluoro, chloro, bromo, (C₁-C₆)alkyl, (C₁-C₆)alkoxyor perfluoro(C₁-C₃)alkyl, preferably fluoro, most preferably wherein R²is in the 4-position of the phenyl ring.

[0010] The present invention also relates to a process for preparing acompound of the formula

[0011] wherein m is an interger from 1-3;

[0012] wherein R² is fluoro, chloro, bromo, (C₁-C₆)alkyl, (C₁-C₆)alkoxyor perfluoro(C₁-C₃)alkyl, comprising, reacting a compound of the formula

[0013] wherein R³ is fluoro, chloro or bromo; and R⁴ is chloro or bromo;

[0014] with a compound of the formula

[0015] wherein m is an interger from 1-3, and R² is fluoro, chloro,bromo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy or perfluoro(C₁-C₃)alkyl;

[0016] in the presence of a base, preferably potassium t-butoxide, and asolvent, preferably N-methylpyrrolidinone, at a temperature from 0° C.to about 150° C.

[0017] The present invention also relates to a process comprising,reacting said compound of formula III with a base, preferably sodiumhydroxide, in a solvent, preferably ethanol, at a temperature from about50° C. to about 100° C. to form a compound of the formula

[0018] wherein

[0019] R is H, Li, Na, K or NH₄, preferably Na, K or Mg, most preferablyNa;

[0020] m is an interger from 1-3; and

[0021] R² is fluoro, chloro, bromo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy orperfluoro(C₁-C₃)alkyl.

[0022] The present invention also relates to a process comprisingreacting a compound of the formula

[0023] wherein

[0024] m is an interger from 1-3;

[0025] R is H, Li, Na, K or NH₄, preferably Na, K, or Mg, mostpreferably Na; and

[0026] R² is fluoro, chloro, bromo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy orperfluoro(C₁-C₃)alkyl;

[0027] with a halogenating agent, preferably thionyl chloride, in asolvent at a temperature from about 0° C. to about 80° C. to form acompound of the formula

[0028] wherein

[0029] m is an interger from 1-3;

[0030] R¹ is halo, preferably chloro, and R² is fluoro, chloro, bromo,(C₁-C₆)alkyl, (C₁-C6)alkoxy or perfluoro(C₁-C₃)alkyl, preferably fluoro,chloro, bromo, more preferably fluoro, most preferably wherein R² is inthe 4-position of the phenyl ring. Preferably, the aforementionedreaction is performed in the presence of a catalyst, preferablydimethylformamide, and a solvent, preferably toluene.

DETAILED DESCRIPTION

[0031] The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated R, R¹,R², R³ and R⁴ in the reaction Schemes and the discussion that follow aredefined as above.

[0032] Scheme 1 refers to the preparation of compounds of formula I,wherein R¹ is halo Compounds of the formula I are useful intermediatesthat can be converted into matrix metalloproteinase inhibitors offormula XI according to the methods of Scheme 2

[0033] Referring to Scheme 1, a compound of the formula I is preparedfrom a compound of the formula II by reaction with a halogenating agent,preferably in the presence of a solvent and a catalyst. Suitablehalogenating agents include oxalyl chloride, thionyl chloridephosphorous oxychloride or phosphorous pentachloride, preferably thionylchloride Suitable catalysts include dimethylformamide. Suitable solventsinclude toluene, methylene chloride or hexane, preferably toluene. Theaforesaid reaction is performed at a temperature of about 0° C. to about70° C., preferably ranging between 25° C. and about 60° C.

[0034] Compounds of the formula II, wherein R is hydrogen, sodium,potassium or ammonium (i.e. H, Li, Na, K or NH₄), preferably sodium, canbe prepared from compounds of the formula III by reaction with a base ina solvent. One of ordinary skill in the art will understand that when Ris Li, Na, K or NH₄, the compound of formula II is ionic, and the groupR possesses a positive charge, and the adjacent oxygen atom possesses anegative charge Suitable bases include sodium hydroxide, potassiumhydroxide or ammonium hydroxide, preferably sodium hydroxide. Suitablesolvents include alcohols such as methanol, ethanol, isopropanol,t-butanol or water and mixtures thereof, preferably ethanol. Theaforesaid reaction is performed at a temperature of about 0° C. to about100° C., preferably ranging between 60° C. to about 80° C.

[0035] The compound of the formula III can be prepared by reaction of acompound of the formula IV with a compound of formula V in the presenceof a base in a solvent. Suitable bases include hindered alkoxide orcarbonate bases such as potassium t-butoxide, sodium t-amyl oxide orpotassium carbonate, preferably potassium t-butoxide. More preferably,two equivalents of potassium t-butoxide are used. Suitable solventsinclude N-methyl-pyrrolidinone, dimethyl formamide, dimethylacetamide ordiglyme, preferably N-methyl-pyrrolidinone. The aforesaid reaction isperformed at a temperature of about 0° C. to about 150° C., preferablyranging between 25° C. and about 130° C. Most preferably the reaction isconducted at a temperature of about 25° C. for about 1 hour and then thetemperature is raised to about 130° C. for about 12 hours.

[0036] Compounds of the formulae IV and V are commercially available orcan be made by methods well known to those of ordinary skill in the art.

[0037] Scheme 2 refers to the preparation of matrix metalloproteinaseinhibiting compounds of formula XI, wherein R⁶ and R⁷ are as defined forcorresponding groups R² and R³ in PCT Publications WO 96/27583 and WO98/07697, published Mar. 7, 1996 and Feb. 26, 1998, respectively.Compounds of formula VI can be made according to PCT Publications WO96/27583 and WO 98/07697, published Mar. 7, 1996 and Feb. 26, 1998 Thesepublications are herein incorporated by reference in their entirety.

[0038] Referring to Scheme 2, compounds of said formula XI are preparedfrom compounds of formula IX by reaction with a chlorinating agent suchas oxalyl chloride or thionyl chloride, preferably oxalyl chloride, anda catalytic amount, preferably about 2%, of N,N-dimethylformamide in aninert solvent such as methylene chloride or toluene to form an in situacid chloride of the formula X that is subsequently reacted with in situformed silylated hydroxylamine. Silylated hydroxylamine formed in situis prepared by reaction of hydroxylamine hydrochloride or hydroxylaminesulfate, preferably hydroxylamine hydrochloride, with trimethylsilylchloride in the presence of a base such as pyridine, 2,6-lutidine, ordiisopropylethylamine, preferably pyridine solvent. Suitable silylatedhydroxylamine formed in situ are selected fromO-trimethylsilylhydroxylamine N,O-bistrimethylsilylhydroxylamine orcombinations thereof. The reaction is performed at a temperature ofabout 0° to about 22° C. (i.e., room temperature) for about 1 to about12 hours, preferably about 1 hour.

[0039] Compounds of the formula IX can be prepared from compounds of theformula VIII by reduction in a polar solvent. Suitable reducing agentsinclude palladium catalysts such as hydrogen over palladium, hydrogenover palladium on carbon or hydrogen over palladium hydroxide on carbon,preferably hydrogen over palladium on carbon. Suitable solvents includetetrahydrofuran, methanol, ethanol and isopropanol and mixtures thereof,preferably ethanol The aforesaid reaction is performed at a temperatureof about 22° C. (i.e., room temperature) for a period of 1 to 7 days,preferably about 2 days.

[0040] Compounds of the formula VIII can be prepared from compounds ofthe formula VII, wherein R⁵ is optionally substituted benzyl, by Michaeladdition to a propiolate ester with a base in a polar solvent. Suitablepropiolates are of the formula H—C≡C—CO₂R⁸ wherein R⁸ is (C₁-C₆)alkyl.Suitable bases include tetrabutylammonium fluoride, potassium carbonate,tertiary amines and cesium carbonate, preferably tetrabutylammoniumfluoride. Suitable solvents include tetrahydrofuran, acetonitrile,tert-butanol, t-amyl alcohols and N,N-dimethylformamide, preferablytetrahydrofuran. The aforesaid reaction is performed at a temperature ofabout −10° C. to about 60° C., preferably ranging between 0° C. andabout 22° C. (i.e., room temperature). The compounds of formula VIII areobtained as mixtures of geometric isomers about the olefinic doublebond; separation of the isomers is not necessary.

[0041] Compounds of the formula VII can be prepared by reaction ofcompounds of the formula VI with compounds of formula I, from Scheme 1,in the presence of a base in a solvent. Suitable bases includetriethylamine, diisopropylethylamine, preferably triethylamine. Suitablesolvents include toluene, or methylene chloride, preferably toluene.

[0042] Final products of the formula XI can also be saponified to thefree acid using a base such as sodium hydroxide in a protic solvent suchas ethanol, methanol or water or a mixture such as water and ethanol,water and toluene, or water and THF. The preferred solvent system iswater and toluene. The reaction is conducted for a period of 30 minutesto 24 hours preferably about 2 hours.

[0043] The compounds of the formula XI which are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids Although such salts must be pharmaceuticallyacceptable for administration to animals, it is often desirable inpractice to initially isolate a compound of the formula XI from thereaction mixture as a pharmaceutically unacceptable salt and then simplyconvert the latter back to the free base compound by treatment with analkaline reagent, and subsequently convert the free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the base compounds of this invention are readily prepared by treatingthe base compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent such as methanol or ethanol. Upon careful evaporation ofthe solvent, the desired solid salt is obtained.

[0044] The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the base compounds of this inventionare those which form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0045] Those compounds of the formula XI which are also acidic innature, are capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the herein described acidic compounds offormula XI. These non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium, calcium andmagnesium, etc These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum product yields.

[0046] The ability of the compounds of formula XI or theirpharmaceutically acceptable salts (hereinafter also referred to as theactive compounds) to inhibit matrix metalloproteinases or the productionof tumor necrosis factor (TNF) and, consequently, demonstrate theireffectiveness for treating diseases characterized by matrixmetalloproteinase or the production of tumor necrosis factor can bedetermined according to in vitro assay tests well known to those ofordinary skill in the art. One example of an assay recognized asdemonstrating that the final products produced by the methods of theinvention is the following Inhibition of Human Collagenase Assay

Biological Assay Inhibition of Human Collagenase (MMP-1)

[0047] Human recombinant collagenase is activated with trypsin using thefollowing ratio. 10 μg trypsin per 100 μg of collagenase. The trypsinand collagenase are incubated at room temperature for 10 minutes then afive fold excess (50 μg/10 μg trypsin) of soybean trypsin inhibitor isadded.

[0048] 10 mM stock solutions of inhibitors are made up in dimethylsulfoxide and then diluted using the following Scheme:

10 mM→120 μM→12 μM→1.2 μM→0.12 μM

[0049] Twenty-five microliters of each concentration is then added intriplicate to appropriate wells of a 96 well microfluor plate. The finalconcentration of inhibitor will be a 1·4 dilution after addition ofenzyme and substrate. Positive controls (enzyme, no inhibitor) are setup in wells D1-D6 and blanks (no enzyme, no inhibitors) are set in wellsD7-D12.

[0050] Collagenase is diluted to 400 ng/ml and 25 μl is then added toappropriate wells of the microfluor plate. Final concentration ofcollagenase in the assay is 100 ng/ml.

[0051] Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH₂) is madeas a 5 mM stock in dimethyl sulfoxide and then diluted to 20 mM in assaybuffer. The assay is initiated by the addition of 50 μl substrate perwell of the microfluor plate to give a final concentration of 10 μM.

[0052] Fluorescence readings (360 nM excitation, 460 nm emission) weretaken at time 0 and then at 20 minute intervals. The assay is conductedat room temperature with a typical assay time of 3 hours.

[0053] Fluorescence vs time is then plotted for both the blank andcollagenase containing samples (data from triplicate determinations isaveraged). A time point that provides a good signal (the blank) and thatis on a linear part of the curve (usually around 120 minutes) is chosento determine IC₅₀ values. The zero time is used as a blank for eachcompound at each concentration and these values are subtracted from the120 minute data. Data is plotted as inhibitor concentration vs % control(inhibitor fluorescence divided by fluorescence of collagenasealone×100). IC₅₀'s are determined from the concentration of inhibitorthat gives a signal that is 50% of the control.

[0054] If IC₅₀'s are reported to be <0.03 μM then the inhibitors areassayed at concentrations of 0 3 μM, 0 03 μM, 0.03 μM and 0.003 μM.

[0055] The following Examples illustrate the preparation of thecompounds of the present invention. Melting points are uncorrected. NMRdata are reported in parts per million (d) and are referenced to thedeuterium lock signal from the sample solvent (deuteriochloroform unlessotherwise specified). Commercial reagents were utilized without furtherpurification THF refers to tetrahydrofuran. DMF refers toN,N-dimethylformamide. Chromatography refers to column chromatographyperformed using 32-63 mm silica gel and executed under nitrogen pressure(flash chromatography) conditions. Room or ambient temperature refers to20-25° C. All non-aqueous reactions were run under a nitrogen atmospherefor convenience and to maximize yields. Concentration at reducedpressure means that a rotary evaporator was used.

EXAMPLE 1 4-(4-Fluorophenoxy)benzenesulfonic Acid 4-Fluorophenyl Ester

[0056] A solution of 14.68 g (0.131 mol, 2.0 equivalents) of potassiumtert-butoxide in 27 mL of dry N-methylpyrrolidinone was treated with asolution of 15.39 g (0.137 mol. 2 1 equivalents) of 4-fluorophenol in 27mL of dry N-methylpyrrolidinone at ambient temperature causing a mildexotherm to 45° C. A solution of 13.81 g (0.065 mol) of4-chlorobenzenesulfonyl chloride in 27 mL of dry N-methylpyrrolidinonewas slowly added to the dark reaction mixture causing a mild exotherm to44° C. The resulting mixture was stirred at room temperature for onehour and then at 130° C. for 11 hours. The cooled reaction mixture wastreated with 162 mL of water, seeded with a trace of4-(4-fluorophenoxy)benzenesulfonic acid 4-fluorophenyl ester, andgranulated at room temperature overnight. The resulting solids werefiltered yielding 20.24 g (85%) of 4-(4-fluorophenoxy)benzenesulfonicacid 4-fluorophenyl ester.

[0057]¹H NMR (CDCl₃) δ 7.74 (dd, J=7 0, 2.0 Hz, 2H), 7.14-6.97 (m, 10H).mp 78-83° C.

EXAMPLE 2 4-(4-Fluorophenoxy)benzenesulfonic Acid, Sodium Salt

[0058] To a slurry of 47.43 g (0.131 mol) of4-(4-fluorophenoxy)benzenesulfonic acid 4-fluorophenyl ester in 475 mLof ethanol was added 13.09 g (0.327 mol, 2.5 equivalents) of sodiumhydroxide pellets. This mixture was heated at reflux for three hours andstirred overnight at room temperature. The resulting solids werefiltered yielding 37.16 g (98%) of 4-(4-fluorophenoxy)benzenesulfonicacid, sodium salt.

[0059]¹H NMR (CD₃OD) δ 7.73-7.78 (m, 2H), 7.05-7.13 (m, 2H), 6.99-7.05(m, 2H), 6 90-6.95 (m, 2H).

EXAMPLE 3 4-(4-Fluorophenoxy)benzenesulfonyl Chloride

[0060] To a slurry of 15.0 g (0.052 mol) of4-(4-fluorophenoxy)benzenesulfonic acid sodium salt, in 150 mL of drytoluene was added 11.3 mL (0 155 mol, 3 equivalents) of thionyl chlorideand 0 04 mL (0.5 mmol, 0 01 equivalents) of dimethylformamide. Theresulting mixture was stirred at room temperature for 48 hours, filteredthrough diatomaceous earth and concentrated under reduced pressure to 40mL. This solution was used without further purification to prepare1-[4-(4-fluorophenoxy)benzenesulfonylamino] cyclopentanecarboxylic acidbenzyl ester.

[0061] A 5.0 mL portion of this solution was concentrated to 1 77 g of4-4-fluorophenoxy)benzenesulfonyl chloride as an oil, corresponding to a96% yield.

[0062]¹H NMR (CDCl₃) δ 7 92-7 97 (m, 2H), 7.01-7.13 (m, 6H). A portionof similarly prepared oil was crystallized from hexane, mp 80° C.

PREPARATION 13-[[4-(4-Fluorophenoxy)benzenesulfonyl]-(1-Hydroxycarbamoylcyclopentyl)amino]PropionicAcid

[0063] A)1-[4-(4-Fluorophenoxy)benzenesulfonylamino]cyclopentanecarboxylic AcidBenzyl Ester

[0064] To a mixture of 12.41 g (0 032 mol) of1-aminocyclopentanecarboxylic acid benzyl ester, toluene-4-sulfonic acidsalt (can be prepared according to the methods of U.S. Pat. No.4,745,124), and 10.0 g (0.035 mol, 1.1 equivalents) of4-(4-fluorophenoxy)benzenesulfonyl chloride in 113 mL of toluene wasadded 11.0 mL (0.079 mol, 2.5 equivalents) of triethylamine. Theresulting mixture was stirred at ambient temperature overnight, washedwith 2N hydrochloric acid (2×100 mL) and brine (100 mL), dried oversodium sulfate, and concentrated to 30 mL. Hexane, 149 mL, was addeddrop-wise over three hours giving a solid precipitate which wasgranulated at 0° C. for one hour and filtered yielding 12.59 9 (85%) of1-[4-(4-fluorophenoxy)benzenesulfonylamino]cyclopentanecarboxylic acidbenzyl ester.

[0065]¹H NMR (CDCl₃) δ 7.78-7 82 (m, 2H), 7.30-7.39 (m, 5H), 7.06-7 12(m, 2H), 6 99-7.04 (m, 2H), 6.93-6.97 (m, 2H), 5 15 (s, 1H), 5.02 (s,2H), 2.04-2.13 (m, 2H), 1 92-1 98 (m, 2H), 1.62-1.69 (m, 4H).

[0066] A 4.0 g sample was granulated in a mixture of 4 mL of ethylacetate and 40 mL of hexanes overnight giving 3.72 g (93% recovery) of1-[4-(4-fluorophenoxy)benzenesulfonylamino] -cyclopentanecarboxylic acidbenzyl ester as light tan solids, mp 97.0-97.5° C.

[0067] B)1-{(2-Ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic Acid Benzyl Ester

[0068] A solution of 25.0 g (53.2 mmol) of1-[4-(4-fluorophenoxy)benzenesulfonylamino]-cyclopentanecarboxylic acidbenzyl ester and 10.8 mL (106 mmol, 2 equivalents) of ethyl propiolatein 200 mL of dry tetrahydrofuran at 1° C. was treated with 53 2 mL (53 2mmol. 1 equivalent) of a solution of tetrabutylammonium fluoride intetrahydrofuran (1M) over 45 minutes. The resulting solution was allowedto warm slowly to ambient temperature and stirred overnight. Thetetrahydrofuran was displaced with toluene at reduced pressure, and thetoluene solution was washed with water and brine, diluted to 600 mL withtoluene, stirred with 90 g of silica gel for three hours, filtered, andconcentrated to 25.14 g (83%) of1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylicacid benzyl ester as an orange oil. ¹ H NMR (CDCl₃) indicated a 1.5:1trans/cis ratio.

[0069] Trans d 7.74-7.78 (m, 2H), 7 72 (d, J=14 Hz, 1H), 7.26-7 36 (m,5H), 6 96-7 12 (m, 4H), 6.78-6.84 (m, 2H), 5.44 (d, J=14 Hz, 1H), 5.11(s, 2H), 4.12 (q, J= 7 1 Hz, 2H), 2 08-2.43 (m, 4H), 1.63-1.80 (m, 4H),1.24 (t, J=7.1 Hz, 3H). Cis d 7.68-7.72 (m, 2H), 7 26-7 36 (m, 5H),6.96-7.12 (m, 4H), 6.86-6.91 (m, 2H), 6.47 (d, J=8.1 Hz, 1H), 5.90 (d,J=8.1 Hz, 1H), 5.11 (s, 2H), 3.93 (q, J=7.2 Hz, 2H), 2.08-2.43 (m, 4H),1.63-1.80 (m, 4H), 1.17 (t, J=7 2 Hz, 3H).

[0070] C)1-{(2-Ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylicAcid

[0071] A solution of 2.50 g (4.4 mmol) of1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylicacid benzyl ester in 25 mL of ethanol was treated with 2.5 g of 50%water wet 10% palladium on carbon catalyst and shaken under 53 psi ofhydrogen for 21 hours. The catalyst was removed by filtration and washedwith ethanol (4×25 mL). The filtrate and washings were combined andconcentrated under vacuum to 1.74 g (82%) of crude1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylicacid□ as a viscous oil.

[0072]¹H NMR (CDCl₃) δ 7.78-7.82 (m, 2H), 6.94-7.09 (m, 6H), 4.09 (q, J=7 2 Hz, 2H), 3.56-3.60 (m, 2H), 2.75-2.79 (m, 2H), 2.33-2.39 (m, 2H),1.93-2.03 (m, 2H), 1 69-1.76 (m, 2H), 1.56-1.63 (m, 2H), 1.22 (t, J=7.2Hz, 3H).

[0073] D) 1-{(2-Ethoxycarbonylethyl)-[4-4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic Acid, Dicyclohexylaminium Salt

[0074] A solution of 3.10 g (6.5 mmol) of crude1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylicacid in 30 mL of ethanol was treated with 1.28 mL (6.5 mmol, 1equivalent) of dicyclohexylamine at ambient temperature producing solidswithin five minutes. This mixture was stirred at ambient temperatureovernight and then at 0° C. for five hours. White solids were isolatedby filtration, washed with 10 mL of cold ethanol, and air dried giving2.89 g (67%) of1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylicacid, dicyclohexylaminium salt

[0075]¹H NMR (CDCl₃) δ 7 86-7.91 (m, 2H), 6.99-7.09 (m, 4H), 6 90-6.94(m, 2H), 5 3 (br s, 2H), 4 07 (q, J=7.1 Hz, 2H), 3.54-3.59 (m, 2H),2.88-2.95 (m, 4H), 2.31-2.38 (m, 2H), 1 95-2.22 (m, 6H), 1.68-1.77 (m,6H), 1.53-1.60 (m, 4H), 1.40-1.50 (m, 4H), 1 21 (t, J=7 1 Hz, 3H),1.14-1 22 (m, 6H). Mp 164.5-165.9° C.

[0076] E)1-{(2-Ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic Acid from1-{(2-Ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylicAcid□, Dicyclohexylaminium Salt

[0077] A solution of 3.0 g (4.5 mmol) of1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylicacid, dicyclohexylaminium salt in 30 mL of dichloromethane was treatedwith 30 mL of 2N hydrochloric acid at ambient temperature causingimmediate precipitation of solids. This mixture was stirred at ambienttemperature for three hours. The solids were filtered, the aqueous phasewas extracted with dichloromethane, and the combined organic phases werewashed with water, dried over sodium sulfate, and concentrated undervacuum to 2.2 g (100%) of1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylicacid as a clear oil.

[0078]¹H NMR (DMSO-d₆) δ 12.68 (bs,1H), 7.76-7.80 (m, 2H), 7.25-7 31 (m,2H), 7 16-7 21 (m, 2H), 7.03-7.08 (m, 2H), 4.01 (q, J=7.1 Hz, 2H),3.48-3.54 (m, 2H), 2.64-2.70 (m, 2H), 2.13-2.21 (m, 2H), 1.90-1.98 (m,2H), 1.52-1.59 (m, 4H), 1.14 (t, J=7.1 Hz, 3H).

[0079] F) 3-{(1-Chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionic Acid Ethyl Ester

[0080] A solution of 7 26 g (15.1 mmol) of1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylicacid in 73 mL of dichloromethane was treated with 1 4 mL (17 mmol, 1.1equivalents) of oxalyl chloride and 0.02 mL (0.3 mmol, 0.02 equivalents)of dimethylformamide at ambient temperature, causing some bubbling, andstirred overnight. The resulting solution of3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionicacid ethyl ester was used for the preparation of3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionicacid ethyl ester without isolation.

[0081] A similarly prepared solution of3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionicacid ethyl ester was concentrated under vacuum to an oil.

[0082]¹H NMR (CDCl₃) δ 7 84-7 87 (m, 2H), 6.97-7.12 (m, 6H), 4.10 (q, J=7.2 Hz, 2H), 3.55-3 59 (m, 2H), 2.68-2.72 (m, 2H), 2.47-2.53 (m, 2H),1.95-2.02 (m, 2H), 1.71-1 76 (m, 4H), 1.24 (t, J=7.2 Hz, 3H).

[0083] G)3-[[4-(4-Fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic Acid Ethyl Ester

[0084] A solution of 1.37 g (19.7 mmol, 1.3 equivalents) ofhydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of drypyridine at 0° C. was treated with 5.8 mL (45 mmol, 3.0 equivalents) oftrimethylsilyl chloride, causing white solids to precipitate, andallowed to warm to ambient temperature overnight. This mixture wascooled to 0° C. and treated with a solution of 7.54 g (15.1 mmol) of3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionicacid ethyl ester in 73 mL of dichloromethane, prepared as describedabove without isolation, causing an exotherm to 8° C. This mixture wasstirred at 0° C. for 30 minutes and at ambient temperature for one hourbefore treating with 50 mL of 2N aqueous hydrochloric acid and stirringat ambient temperature for one hour. The aqueous phase was extractedwith dichloromethane and the combined organic phases were washed with 2Naqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionicacid ethyl ester in dichloromethane was used for the preparation of3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid without isolation.An aliquot was concentrated to a foam.

[0085]¹H NMR (DMSO-d₆) δ 10.37 (s, 1H), 8 76 (s, 1H), 7 74-7.79 (m, 2H),7 24-7 30 (m 2H), 7.14-7 20 (m, 2H), 7.01-7 05 (m, 2H), 3 99 (q, J=7.1Hz, 2H), 3 42-3.47 (m, 2H), 2 62-2.67 (m, 2H), 2.16-2.23 (m, 2H),1.77-1.85 (m, 2H), 1.43-1 52 (m, 4H), 1 13 (t, J=7 1 Hz, 3H)

[0086] A similarly prepared solution was concentrated under vacuum to 671 g (89%) of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester as a harddry foam.

[0087] H)3-[[4-(4-Fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic Acid

[0088] A solution of 7.48 g (15.1 mmol) of3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionicacid ethyl ester in dichloromethane was concentrated by rotaryevaporation with the addition of 75 mL of toluene. This solution wastreated with 75 mL of water, cooled to 0° C., and treated with 6.05 g(151 mmol, 10 equivalents) of sodium hydroxide pellets over 10 minuteswith vigorous stirring. This mixture was stirred for 15 minutes at 0° C.and warmed to ambient temperature over one hour. The aqueous phase wasseparated, diluted with 7.5 mL of tetrahydrofuran, cooled to 0° C., andtreated with 33 mL of 6N aqueous hydrochloric acid over 20 minutes. Thismixture was stirred with 75 mL of ethyl acetate at 0° C. to ambienttemperature, and the ethyl acetate phase was separated and washed withwater. The ethyl acetate solution was slowly treated with 150 mL ofhexanes at ambient temperature causing solids to precipitate, andstirred overnight. Filtration yielded 5.01 g of3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionicacid as a white solid (71% yield from1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylicacid).

[0089]¹H NMR (DMSO-d₆) δ 12.32 (s, 1H), 10.43 (s, 1H), 8.80 (s, 1H), 782 (d, J=8 6 Hz, 2H), 7.28-7.35 (m, 2H), 7.20-7.26 (m, 2H), 7.08 (d,J=8.9 Hz, 2H), 3.44-3.49 (m, 2H), 2 61-2.66 (m, 2H), 2.24-2.29 (m, 2H),1.86-1.90 (m, 2H), 1.54-1.55 (m, 4H). mp 162.9-163 5° C. (dec).

1. A compound of the formula

wherein R is H, Li, Na, K, Mg, or NH₄.
 2. A compound of the formula

wherein m is an interger from 1-3; R² is fluoro, chloro, bromo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy or perfluoro(C₁-C₃)alkyl.
 3. A compoundaccording to claim 2 wherein R² is fluoro.
 4. A compound according toclaim 3 wherein R² is in the 4-position of the phenyl ring.
 5. A processfor preparing a compound of the formula

wherein m is an interger from 1-3; R² is fluoro, chloro, bromo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy or perfluoro(C₁-C₃)alkyl; comprising,reacting a compound of the formula

wherein R³ is fluoro, chloro or bromo; and R⁴ is chloro or bromo; with acompound of the formula

wherein m is an interger from 1-3; and R² is fluoro, chloro, bromo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy or perfluoro(C₁-C₃)alkyl, in the presence ofa base and a solvent at a temperature from 0° C. to about 150° C.
 6. Aprocess according to claim 5 wherein said base is potassium t-butoxideand said solvent is N-methylpyrrolidinone.
 7. A process according toclaim 5 further comprising, reacting said compound of formula III with abase in a solvent at a temperature from about 50° C. to about 100° C. toform a compound of the formula

wherein m is an interger from 1-3; R is H, Li, Na, K or NH₄; and R² isfluoro, chloro, bromo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy orperfluoro(C₁-C₃)alkyl.
 8. A process according to claim 7 wherein saidbase is sodium hydroxide and said solvent is ethanol.
 9. A processaccording to claim 7 further comprising reacting a compound of theformula

wherein m is an interger from 1-3; R is H, Li, Na, K or NH₄, and R² isfluoro, chloro, bromo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy orperfluoro(C₁-C₃)alkyl; with a halogenating agent in a solvent at atemperature from about 0° C. to about 80° C. to form a compound of theformula

wherein R¹ is halo and m is an integer from 1-3.
 10. A process accordingto claim 9 wherein R¹ is chloro.
 11. A process according to claim 9wherein R² is fluoro.
 12. A process according to claim 9 wherein R² isin the 4-position of the phenyl ring
 13. A process according to claim 9wherein said halogenating agent is thionyl chloride.
 14. A processaccording to claim 9 further comprising the addition of a catalyst and asolvent.
 15. A process according to claim 14 wherein said catalyst isdimethylformamide and said solvent is toluene.